Abbreviations/Key
5HT2A, 5HT2C, 5HT3Neurophysiology of Dopamine
Pathway | Function | Symptoms of Dysregulation |
---|---|---|
Mesolimbic Midbrain reticular formation → limbic cortex | Pleasure, motivation and reward | ↑Dopamine: “positive” symptoms of psychosis (delusions, hallucinations) |
Mesocortical system Midbrain reticular formation → prefrontal cortex | Affect, executive function, concentration | ↓Dopamine: depression; “negative” symptoms of psychosis (apathy, anhedonia and cognitive blunting) |
Nigrostriatal system Substantia nigra → corpus striatum | Extrapyramidal motor system | ↓Dopamine: Parkinson’s disease, drug-induced parkinsonism, akathisia, dystonia, restless legs ↑Dopamine: dyskinesia |
Tuberoinfundibular system | Dopaminergic inhibition of prolactin secretion | ↓Dopamine: hyperprolactinemia |
Thalamic dopamine pathway Multiple origins → thalamus | Sleep and arousal through sensory gating | |
Area postrema | Emetogenesis | ↑Dopamine: nausea and vomiting |
- •“positive” symptoms (delusions and hallucinations) result from dopamine excess in the mesolimbic system
- •“negative” symptoms (apathy, anhedonia and cognitive blunting) result from dopamine deficit in the mesocortical system.
- •nigrostriatal system, part of the extrapyramidal motor system:
- ➢D2 antagonists initially cause underactivity, similar to Parkinson’s disease → acute extrapyramidal symptoms
- ➢subsequent adaptation to D2 antagonism leads to D2 receptor upregulation → tardive dyskinesia
- ➢
- •tuberoinfundibular system; D2 antagonists cause hyperprolactinemia → sexual dysfunction.
Pharmacology
- •typical:
- ➢phenothiazines: chlorpromazine, levomepromazine (not USA), perphenazine, prochlorperazine, promazine, trifluoperazine
- ➢butyrophenones: haloperidol
- ➢
- •atypical: aripiprazole, clozapine, olanzapine, quetiapine, risperidone.
- •muscarinic, causing dry mouth, constipation, etc.
- •adrenergic, causing postural hypotension
- •histaminic, causing drowsiness.
National Institute of Mental Health (NIMH). NIMH’s psychoactive drug screening program. 2006. University of North Carolina. Available from http://pdsp.med.unc.edu/indexR.html.
D2 | 5HT2A | 5HT2C | 5HT3 | H1 | α1 | α2 | AChM | |
---|---|---|---|---|---|---|---|---|
Aripiprazole | +++PA | +++ | +++ | - | +++ | +++ | ++ | - |
Chlorpromazine | +++ | +++ | ++ | - | +++ | +++ | + | ++ |
Clozapine | + | +++ | ++ | + | +++ | + | + | +++ |
Haloperidol | +++ | + | - | - | - | ++ | - | - |
Levomepromazine (not USA) | ++ | +++ | +++ | +++ | + | ++ | ||
Perphenazine | +++ | +++ | + | +++ | ++ | + | - | |
Prochlorperazine | +++ | ++ | + | - | ++ | ++ | - | + |
Olanzapine | ++ | +++ | + | + | + | ++ | + | ++ |
Quetiapine | + | + | + | - | ++ | + | ++ | - |
Risperidone | +++ | +++ | ++ | - | ++ | + | +++ | - |
- •5HT2 receptor antagonism
- •D2 partial agonism
- •lower affinity and shorter duration D2 antagonism.
Oral Bioavailability (%) | Time to Peak Plasma Concentration | Half-Life (h) | Metabolism (Predominant P450 Isoenzyme) | |
---|---|---|---|---|
Chlorpromazine | 10–25 | 2–4 h (PO) | 30 | CYP2D6 |
Clozapine | 50–60 | 2 h | 12 | CYP1A2, CYP3A4 |
Haloperidol | 60–70 | 2–6 h (PO) 10–20 min (SC) | 13–35 | Multiple |
Levomepromazine (not USA) | 40 | 1–3 h (PO) 30–90 min (SC) | 15–30 | Multiple |
Olanzapine | 60 | 5–8 h | 34 (52) | CYP1A2, CYP2D6 |
Prochlorperazine | 6 14 (buccal) | 4 h (PO) 4–8 h (buccal); shorter with multiple doses | 15–20 | Multiple |
Quetiapine | 100 | 1.5 h | 7 (10–14) (12) | CYP3A4 |
Risperidone | 99 | 1–2 h | 24 | CYP2D6 |
Cautions
Stroke Risk
Epilepsy
Parkinsonism and Parkinson’s Disease
- •domperidone (available as a suppository)
- •ondansetron
- •scopolamine (hyoscine) hydrobromide, but may cause delirium.
- •look for potentially reversible causes of delirium, e.g., sepsis
- •consider a trial reduction of antiparkinsonian medication:
- ➢reduce dopamine receptor agonists and antimuscarinic agents initially
- ➢dopamine precursors, e.g., levodopa, are less likely to cause psychosis.32
- ➢
Drug Interactions
Undesirable Effects
- Parkinsonism, akathisia, dystonia, tardive dyskinesia.33
Extrapyramidal syndromes
- More common with typicals and risperidone
- Hyperprolactinemia resulting in amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, osteoporosis.
- More common with atypicals, particularly olanzapine and clozapine
- Weight gain.
- Dyslipidemia, possibly associated with weight gain.
- Type 2 diabetes mellitus, both new onset and exacerbation of pre-existing disease; risk independent of weight gain.
Metabolic effects20, 34
- QT prolongation: dose-related, affected by presence of other risk factors, highest risk with thioridazine (withdrawn) and ziprasidone.20,35
- Venous thromboembolism; risk possibly highest with atypicals.36
- Stroke and increased risk of death in elderly patients (see Cautions).
- Postural hypotension (α-adrenergic antagonism), particularly phenothiazines and clozapine; also seen with quetiapine and risperidone.
Cardiovascular effects
- Reduced seizure threshold (see Cautions).
- Antimuscarinic effects; more with phenothiazines and clozapine.
- Neuroleptic (antipsychotic) malignant syndrome (see below).
- Agranulocytosis is seen in about 1% of patients taking clozapine, generally after 3–6 months.
Miscellaneous20
Neuroleptic (Antipsychotic) Malignant Syndrome
- Severe muscle rigidity
- Pyrexia ± sweating
Essential
- Muteness γ stupor
- Tachycardia and elevated/labile blood pressure
- Leukocytosis
- Raised plasma creatine phosphokinase ± other evidence of muscle injury, e.g., myoglobinuria
Additional
- •discontinuation of the causal drug
- •prescription of a muscle relaxant, e.g., a benzodiazepine
- •in severe cases, prescription of bromocriptine.43
Use of Antipsychotics in Palliative Care
Nausea and vomiting
Delirium
Agitation and challenging behaviors in dementia
- •intercurrent infections
- •pain and/or other distressing symptoms
- •environmental factors.
Committee on Safety of Medicines. Antipsychotic drugs and stroke. 2004. Available from: http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON1004298.
Health Canada. Increased mortality associated with the use of atypical antipsychotic drugs in elderly patients with dementia. Notice to healthcare professionals. 2005. Available from www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2005/atyp-antipsycho_hpc-cps-eng.php.
US Food and Drug Administration. Alert. Information on antipsychotics (6/16/2008). 2008. Available from www.fda.gov/Drugs,
- •haloperidol
- •atypicals, e.g., olanzapine, quetiapine, risperidone
- •cholinesterase inhibitors (benefit is marginal, but may be better tolerated).64
Intractable hiccup
Refractory depression
National Institute for Health and Clinical Excellence (NICE). Clinical guideline 90. Depression. London: NICE, 2009. Available from www.nice.org.uk.
Pain
Switching Antipsychotics
Drug | Dose (mg) |
---|---|
Chlorpromazine | 100 |
Promazine | 100 |
Perphenazine | 8 |
Trifluoperazine | 5 |
Haloperidol | 3 |
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Article info
Publication history
Footnotes
Series Co-Editors: Andrew Wilcock, DM, FRCP, and Robert Twycross, DM, FRCP